Israeli Study Gains Pace in Seeking Treatment for ALS

Any drug remains a long way away, but Tel Aviv University researchers have identified a molecule for stopping the secretion of toxins and hopefully slowing the development of Lou Gehrig’s disease

Dr. Eran Perlson of Tel Aviv University’s Sackler Faculty of Medicine, May 23, 2018.
Meged Gozani

A discovery by Tel Aviv University researchers helps show the mechanism of amyotrophic lateral sclerosis – Lou Gehrig’s disease – and could lead to the first effective treatment for the fatal disease in which nerve cells die.

In an article published a week ago in The Journal of Neuroscience, the researchers say the motor neurons of ALS patients are damaged due to the toxins secreted by muscles. The scientists propose a new approach to delay the disease: the development of a molecule that paralyzes the genes that cause the secretion of toxins.

The researchers show positive initial results in lab tests on human cells and mice – reason for cautious optimism, even though the development of a drug based on the approach is still far off.

“ALS is a violent and fatal degenerative disease for which there is no effective treatment at present. It usually attacks older people but can also appear at an early age,” said Dr. Eran Perlson of Tel Aviv University’s Sackler Faculty of Medicine.

“The patients gradually lose their ability to move, speak and swallow, and in the end they die as a result of the paralysis of the respiratory muscles. The paralysis in ALS is a result of the atrophy and death of the motor neurons, which send orders from the brain to the muscles,” said Perlson, who led the study.

ALS is considered the most serious degenerative disease. It damages the peripheral motor neurons through which the brain activates most of the body’s voluntary muscles. The cells are destroyed and are incapable of activating the muscles, eventually leading to total paralysis.

Up to our fingertips

Lou Gehrig giving a famous speech at Yankee Stadium in New York in 1939. He died two years later
AP

Perlson says the first site damaged is the nerve fiber, or axon, at its point of encounter with a muscle. Researchers haven’t understood how and why that happens, and mainly why, of all the body's nerve cells, the motor neurons are the ones that sustain damage.

“Therefore, an understanding of the mechanisms that cause the disease is a crucial basis for the future development of suitable drugs,” Perlson said.

The study, which was conducted in Perlson’s laboratory, was carried out by doctoral students Roy Maimon and Ariel Ionescu, Prof. Miguel Weil and other Tel Aviv University researchers, in cooperation with Prof. Oded Behar of Hadassah University Hospital in Jerusalem.

The idea of the involvement of “neighbor cells” of nerve cells in the disease isn’t new and has been raised in the past regarding various types of brain cells. But the current study is about the effect of the toxicity of muscle cells on nerve cells of the peripheral nervous system, which is distributed in our bodies up to our fingertips.

The research’s first stage included the development of a silicon chip that allows the growing of nerve and muscle cells in the lab for experiments. Already at the start of the study the researchers noticed that healthy muscle cells secrete substances that cause the growth of nerve cells, while the muscle cells of ALS patients cause the disintegration and degeneration of nerve cells. The researchers concluded that the muscle cells of ALS patients secrete toxins that disrupt the so-called neuromuscular junctions.

In a scan of the muscle proteins secreted in a disease situation, compared to those of healthy muscle, there was a particularly high level of proteins called semaphorins, a toxin known to be active when a fetus’ nervous system develops. These proteins get rid of superfluous axons that are created in the fetal stage.

A molecule that reduces toxicity

This protein also turns up, for example, in Parkinson’s disease, and after a stroke or spinal damage. Later it was found that the muscle cells of ALS patients secrete a large amount of semaphorins, which helps destroy the nerve cells. But it soon became clear that semaphorins are only part of the problem; other toxins secreted in the muscle cells of ALS patients also damage the connection between nerve cells and muscles.

This finding led to a search for a molecule that would delay the secretion of most of the toxins that damage nerve cells, and thereby delay the disease. A molecule called miR126 was identified capable of reducing toxicity levels in muscle cells. When this molecule was added to the silicon chip, it significantly improved the condition of the axons.

“At that stage we started to switch to a live model,” Perlson said. His team injected miR126 into mice.

“And we did in fact see an improvement in their condition. The level of toxicity declined; an improvement was seen in the muscle tissue and the nerve-muscle encounter,” he said, adding that the mice’s ability to walk improved.

“We believe that our discovery is a real breakthrough on the way to developing effective drugs for ALS, and later perhaps for other neurodegenerative diseases such as Alzheimer’s and Parkinson’s that are characterized by the destruction of various types of nerve cells,” Perlson said.

“The next stage is a continuation and deepening of the study to gain a better understanding of the operational mechanism, and to examine its effect in various environments in the central and peripheral nervous systems.”

ALS usually progresses quickly and gradually damages the muscles controlling the limbs, swallowing, talking and breathing. The frequency of the disease is 1 in 10,000 people. In Israel, according to IsrA.L.S., the Israel ALS Research Association, there are currently between 600 and 700 patients.

“Although there have been many attempts, there is still no breakthrough treatment for the disease, there’s no real news for patients. In recent years there have been much larger studies, and much more money is being channeled to study the disease,” Perlson said.

“We know more about the disease than in the past, and there are all kinds of new ideas and directions, but the bottom line is there is no treatment as of yet. The main reason is that we don’t understand the basic mechanisms that cause the destruction of nerve cells and motor neurons.”